The innate immune system comprises cells and mechanisms that defend the host from infection by other organisms in a non-specific manner. In addition to the role as the first line of defense against infection, the innate immune response plays a vital role in killing cancerous cells. Natural killer (NK) cells, a key component of the innate immune response, represent 10-15% of-circulating lymphocytes in the blood. NK cells possess potent cytolytic activity against virus- or pathogen-infected cells and tumor cells by releasing cytotoxic granules that can spontaneously kill target cells. NK cells also possess immunoregulatory functions that influence adaptive immunity by modulating the activity of other immune cells. Aberrant immune responses can lead to excessive inflammation and autoimmune reactions, leading to diseases such as arthritis and allergies. Therefore, modulation of NK cells could lead to a more robust or properly regulated immune response, enhancing immune response to infected cells, enhanced tumor clearance, decreased inflammatory and allergic responses, and increase efficacy of cancer vaccines.
Given its critical role in immunity and tumor targeting, several strategies for the therapeutic use of NK cells has been proposed and tested. Adoptive transfer of NK cells from autologous or allogeneic donors have been used in the clinic to neat various types of cancers, with mixed results. Attempts to enhance the activity of NK cells for adoptive transfer have treated the cells with cytokines, such as IL-2 and IL-12, prior to injecting the cells into the patient. Adoptive transfer of NK cells to make them more active also has been attempted via genetic manipulation of the NK cells prior to injection into patient. Adoptive transfer poses technical and safety concerns, such as increased risk of spreading disease from the donor to host, intense donor screening and selection, technical expertise in handling and manipulation of the cells, great expense, and potential long term health risks to the patient.
Other strategies to manipulate NK activity that has been pursued are the use of immunomodulatory drugs such as thalidomide and cytokines such as IL-2, IL-12, IL-15, IL-18, IL-21 and type I IFNs, to stimulate the patients endogenous NK cells. However, toxicity of cytokines in high doses required for effective stimulation of NK cells prohibits then systemic administration. As such, a novel strategy for activating NK cells with better efficacy and less toxicity is warranted, and described within.